chr6-33069898-C-A

Variant names:

• chr6-33069898-C-A
• rs10214910
• NM_033554.4:c.101-12G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033554.4(HLA-DPA1):​c.101-12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,557,554 control chromosomes in the GnomAD database, including 49,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.32 (11147 hom., cov: 32)
  • Exomes 𝑓: 0.19 (38725 hom.)
• Consequence: HLA-DPA1 NM_033554.4 intron
• Scores: Splicing: ADA: 0.00004156
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.274
• Publications: 26 publications found

Genes affected

HLA-DPA1 (HGNC:4938): (major histocompatibility complex, class II, DP alpha 1) HLA-DPA1 belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta (DPB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033554.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DPA1	NM_033554.4	MANE Select	c.101-12G>T		intron	N/A	NP_291032.2
	HLA-DPA1	NM_001242524.2		c.101-12G>T		intron	N/A	NP_001229453.1	P20036
	HLA-DPA1	NM_001242525.2		c.101-12G>T		intron	N/A	NP_001229454.1	X5CKE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DPA1	ENST00000692443.1	MANE Select	c.101-12G>T		intron	N/A	ENSP00000509163.1	P20036
	HLA-DPA1	ENST00000419277.5	TSL:6	c.101-12G>T		intron	N/A	ENSP00000393566.1	P20036
	HLA-DPA1	ENST00000923943.1		c.101-12G>T		intron	N/A	ENSP00000594002.1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48939 AN: 151828 Hom.: 11100 Cov.: 32

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.232 AC: 53652 AN: 231370 AF XY: 0.228

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.686

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.195 AC: 273453 AN: 1405608 Hom.: 38725 Cov.: 32 AF XY: 0.197 AC XY: 137206 AN XY: 698164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.630 AC: 19271 AN: 30600

American (AMR) AF: 0.177 AC: 7485 AN: 42352

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4459 AN: 25196

East Asian (EAS) AF: 0.631 AC: 23985 AN: 38028

South Asian (SAS) AF: 0.298 AC: 23748 AN: 79716

European-Finnish (FIN) AF: 0.0991 AC: 5128 AN: 51752

Middle Eastern (MID) AF: 0.205 AC: 1146 AN: 5596

European-Non Finnish (NFE) AF: 0.163 AC: 175093 AN: 1074670

Other (OTH) AF: 0.228 AC: 13138 AN: 57698

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.323 AC: 49044 AN: 151946 Hom.: 11147 Cov.: 32 AF XY: 0.320 AC XY: 23752 AN XY: 74284

African (AFR) AF: 0.611 AC: 25286 AN: 41388

American (AMR) AF: 0.260 AC: 3966 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3464

East Asian (EAS) AF: 0.688 AC: 3556 AN: 5170

South Asian (SAS) AF: 0.344 AC: 1657 AN: 4814

European-Finnish (FIN) AF: 0.103 AC: 1084 AN: 10566

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11966 AN: 67972

Other (OTH) AF: 0.335 AC: 707 AN: 2110

Alfa AF: 0.237 Hom.: 17893

Bravo AF: 0.346

Asia WGS AF: 0.463 AC: 1608 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.66
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10214910; hg19: chr6-33037675;